HETEROCYCLES

Short Paper | Regular issue | Vol. 83, No. 5, 2011, pp. 1121-1127
Received, 21st October, 2010, Accepted, 3rd March, 2011, Published online, 10th March, 2011.
DOI: 10.3987/COM-10-12086

■ Microwave-Assisted Synthesis of 3,5-Disubstituted Thiohydantoins Using Functional Ionic Liquid as Soluble Support

Chen Zhuo,* Dong Xian, Xie Hui, and Li Mei

School of Chemistry and Material Science, Guizhou Normal University, Guiyang, 550001, China

Abstract

A new approach for the syntheses of 3,5-disubstituted thiohydantoins was described using functionalized ionic liquid as soluble support. The products were obtained in good yields and purities after cyclization-cleavage from the ionic-liquid-supported under microwave irradiation, the ionic-liquid-supported species can there be purified from the reaction mixture by simple washing, and no chromatographic purification were needed during the synthesis.

Organic synthesis using insoluble solid polymer resin as support was first proposed by Merrifield more than four decades ago1 and has since been applied extensively in numerours areas.2,3 However, the solid phase synthesis approach suffers from some disadvantages. This has led to alternative methodologies with the aim of restoring homogeneous reaction conditions. Recently, more attentions in ionic liquids (ILs) research has been paid on the functionalized ionic liquids with special task, which have been introduced as soluble supports in liquid-phase organic synthesis.4 Substrates anchored on ionic liquids are expected to retain their reactivities, and allow the use of conventional spectroscopic analysis during the synthetic process. Finally the products could be cleavaged from the ionic liquid support. Recent reports from several groups have successfully demonstrated the efficiency of ionic liquid supported synthesis for small molecules5 and peptides.6 Microwave irradiation has become an established tool in organic synthesis. Hoffmann et al. reported ionic liquids could efficiently absorb microwave energy by which the reaction rate could be accelerated remarkably.7
3,5-Disubstituted thiohydantoins have been identified to possess a wide range of biological activities.8 As a part of our ongoing efforts in using ionic liquid as eco-friendly medium in condensation reaction,9 we report herein a new synthetic approach of 3,5-disubstituted thiohydantoins under microwave irradiation using the functionalized ionic liquid (1) as soluble supports, which incorporate both the thiourea and imidazole functionalities (Scheme 1).

For this study, 1-(2-hydroxyethyl)-1-methylimidazolium tetrafluoroborate 1 was prepared according to the literature.10,11 As shown in Scheme 1, the functionalized ionic liquid 1 dissloved in acetonitrile was coulped with a t-Botoxycarbonyl (BOC) amino acid under dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) activation at room temperature for 18 hours. Ionic-liquid-supported Boc-amino acid was removed the Boc group using trifluoroacetic acid (TFA) in dichloromethane to yield 2, which was reacted with an isothiocyanate to provide the ionic-liquid-supported thiourea 3. The reaction was conveniently monitored via the ninhydrin test.12 The desired 3,5-disubstituted thiohydantoins 4 was obtained via intramolecular cyclization with concomitant cleavage from IL support using diethylamine (DEA) under microwave irradiation for 45 min.
To establish the scope of this reaction, various amino acids and isothiocyanates were investigated. The results were summarized in Table 1, all the products were characterized by 1H NMR, IR spectrum and ESI-MS. The method was found to be generally applicable, all the products were obtained in good to excellent yields.
In summary, we have successfully performed the microwave-assisted synthesis of 3,5-disubstituted thiohydantoins using hydroxyl-functionalized ionic liquids as soluble support. Our method represents an attractive alternative to the classical solid- and fluorous-phase synthesis strategies including being environmentally more benign, the isolation and purification of intermediates more easy, the shorter reaction times, the higher yields, no need for the use of large molar excess of reagents, without the need for chromatographic purification. It is well believed that this methodology constitutes an attractive avenue for the rapid synthesis of heterocyclic products.

EXPERIMENTAL
The 1H NMR spectra were recorded on Brucker Avance DMX-500 MHz instrument with CDCl3 or dimethyl sulfoxide (DMSO-d6) as solvent and tetramethylsilane (TMS) as the internal standard, and the chemical shifts are expressed in parts per million (ppm). Electroscopy ionization-mass spectrometry (ESI-MS) data were recorded on a Bruker Esquire 3000t spectrometer. The infrared (IR) spectra were recorded on a Bruck Vector 200 spectrophotometer (KBr film). Elemental analyses were perform on a Carlo Erba EA 1106 instrument. The microwave irradiation was performed in a 5 mL flask equipped with mechanical stirrer in a Biotage Imitiator 8 microwave oven.

General procedure for the synthesis of the 3,5-disubstituted thiohydantoins 4:
Esterification (Loading) Step: Dicyclohexylcarbodiimide (DCC, 1 M in CH2Cl2, 10 mL, 10 mmol) was added to a mixture of ionic liquid (1.07 g, 5 mmol), Boc-amino acid (10 mmol), and (dimethylamino)pyridine (0.25 g, 2 mmol) in dry MeCN (25 mL). The mixture was stirred vigorously for 18 h at room temperature under nitrogen and filtrated through a plug of Celite. The Celite plug was rinsed with MeCN, and the combined organic phase was concentrated in vacuum. The crude residue was washed first with Et2O (20 mL×3) and then dissolved in CH2Cl2 and washed with 2 M HCl (10 mL×3). The organic phase was dried over Na2SO4 and concentrated to afford 1.95 g (91%) of ionic-liquid-supported Boc-amino acid as a pale yellow oil.

Forming Step (Deprotection and Coupling): TFA (10 mL) was added to a solution of ionic-liquid-supported Boc-amino acid (2 mmol) in CH2Cl2 (10 mL). The reaction was stirred at room temperature under nitrogen for 0.5 h. Upon concentration under reduced pressure, the residue was washed twice with Et2O and dried on a vacuum line to yield the deprotected ionic-liquid-supported amino acid 2 as a TFA salt. The ionic-liquid-supported Boc-amino acid was then dissolved together with isothiocyanate (3 mmol, 1.5 eq) and N,N-diisopropylethylamine (DIEA) (3 mmol, 1.5 eq) in dry MeCN, and the resulting reaction mixture was stirred at 35 ºC under nitrogen atmosphere for 8 h. Completeness of the coulping was verified by the ninhydrin test. The solvent was removed under vacuum, and the residue was washed with Et2O (20 mL×3) to afford the ionic-liquid-supported thiourea 3 as yellow oil.

Cyclization/Cleavage Step: A mixture of the ionic-liquid-supported thiourea (1 mmol) from the previous step and commercial diethylamine (2 mmol, 2 eq) was dissolved in MeOH (5 mL). The resulting solution was placed in a cylindrical quartz reactor. Then reactor was introduced into a Biotage Imitiator 8 microwave oven. The liquid mixture was stirred mechanically and was irradiated at 120 ºC for a reaction time ranging 45 min. After microwave dielectric heating, the crude reaction mixture was allowed to cool down at 25 ºC. The resulting solution was concentrated by rotary evaporation and the crude solution was extracted with Et2O (20 mL ×3). Concentration of the combined Et2O extracts under reduced pressure afforded the desired 3,5-disubstituted thiohydantoins 4.

5-Benzyl-3-phenyl-2-thioxoimidazolidin-4-one (4a). 1H NMR (CDCl3): δ = 7.46 (m, 2H), 7.38 (m, 3H), 7.33(m, 3H), 7.05 (m, 2H), 4.55 (q, 1H, J = 4 Hz, J = 7.51 Hz), 3.38 (m, 1H), 3.14 (m, 1H). IR (neat): 3166.53, 1750.66, 1512.92, 1403.19, 1333.59, 1262.06, 1187.65, 1097.07 cm-1. ESIMS, m/z: 283 (MH+). Anal. Calcd for C16H14N2OS: C, 68.06; H, 5.00; N, 9.92. Found: C, 68.15; H, 5.09; N, 9.81.
5-Benzyl-2-thioxo-3-(m-tolyl)imidazolidin-4-one (4b). 1H NMR (CDCl3): δ = 7.41 (m, 7H), 7.02 (m, 2H), 4.52 (m, 1H), 3.35 (m, 1H), 3.10 (m, 1H), 2.37 (s, 3H). IR (neat): 3415.75, 2923.17, 1740.49, 1648.89, 1496.01, 1392.65, 1258.01, 1191.04, 735.08cm-1. ESIMS, m/z: 297 (MH+). Anal. Calcd for C17H16N2OS: C, 68.89; H, 5.44; N, 9.45. Found: C, 68.78; H, 5.53; N, 9.36.
5-Benzyl-3-butyl-2-thioxoimidazolidin-4-one (4c). 1H NMR (CDCl3): δ = 9.16 (s, 1H), 7.30 (m, 5H), 5.30 (s, 1H), 3.48 (s, 2H), 3.02 (d, 2H, J = 6 Hz), 1.33 (m, 7H). IR (neat): 3446.12, 2925.06, 2856.66, 1680.08, 1457.49, 1391.21, 1201.59 cm-1. ESIMS, m/z: 263 (MH+). Anal. Calcd for C14H18N2OS: C, 64.09; H, 6.91; N, 10.68. Found: C, 64.21; H, 7.02; N, 10.59.

5-Isopropyl-3-phenyl-2-thioxoimidazolidin-4-one (4d). 1H NMR (CDCl3): δ = 7.38 (brs, 1H), 7.38 (m, 3H), 7.31 (m, 2H), 4.71 (d, 1H, J = 4 Hz), 2.38 (m, 1H), 1.15 (d, 3H, J = 7 Hz), 1.12 (3H, d, J = 7 Hz). IR (neat): 3178.90, 2964.12, 1756.58, 1681.85, 1513.73, 1404.83, 1348.02, 1266.60, 1183.70, 759.03cm-1. ESIMS, m/z: 235 (MH+). Anal. Calcd for C12H14N2OS: C, 61.51; H, 6.02; N, 11.96. Found: C, 61.58; H, 6.09; N, 11.85.
5-Isopropyl-2-thioxo-3-(m-tolyl)imidazolidin-4-one (4e). 1H NMR (CDCl3): δ = 7.50 (brs, 1H), 7.37 (m, 1H), 7.27 (s, 1H), 7.11 (m, 2H), 4.16 (d, 1H, J = 4 Hz), 2.40 (s, 3H), 2.33 (m, 1H), 1.22 (d, 3H, J = 6.8 Hz), 1.03–1.05 (d, 3H, J = 6.8 Hz). IR (neat): 3178.90, 2964.12, 1756.58, 1681.85, 1513.73, 1404.83, 1348.02, 1266.60, 1183.70, 759.03cm-1. ESIMS, m/z: 249 (MH+). Anal. Calcd for C13H16N2OS: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.95; H, 6.58; N, 11.21.
3-Butyl-5-isopropyl-2-thioxoimidazolidin-4-one (4f). 1H NMR (CDCl3): δ = 7.50 (brs, 1H), 7.26 (m, 2H), 7.27 (s, 1H), 7.11 (m, 2H), 4.16 (d, 1H, J = 4 Hz), 2.40 (s, 3H), 2.33 (m, 1H), 1.22 (d, 3H, J = 6.8 Hz), 1.03–1.05 (d, 3H, J = 6.8 Hz). IR (neat): 3441.09, 2966.12, 2864.59, 2510.67, 1681.83, 1464.29, 1200.35, 1135.50, 1060.51, 794.61cm-1. ESIMS, m/z: 215 (MH+). Anal. Calcd for C10H18N2OS: C, 56.04; H, 8.47; N, 13.07. Found: C, 56.01; H, 8.56; N, 13.01.
5-Isobutyl-3-phenyl-2-thioxoimidazolidin-4-one (4g). 1H NMR (CDCl3): δ = 7.28 (m, 3H), 3.48 (s, 1H), 3.40 (m, 2H), 3.24 (m, 1H), 1.74 (m, 1H), 1.58 (m, 2H), 1.11 (d, 6H, J = 7 Hz). IR (neat): 3428.07, 2928.40, 1635.83, 1528.44, 1447.63, 1405.18, 1352.36, 1316.54, 1262.23, 756.86cm-1. ESIMS, m/z: 249 (MH+). Anal. Calcd for C13H16N2OS: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.76; H, 6.56; N, 11.22.
5-Isobutyl-2-thioxo-3-(m-tolyl)imidazolidin-4-one (4h). 1H NMR (CDCl3): δ = 7.26 (m, 1H), 7.10 (m, 4H), 3.48 (m, 1H), 2.40 (s, 3H), 1.71 (m, 2H), 1.67 (m, 1H), 1.09 (d, 6H, J = 7 Hz). IR (neat): 3332.47, 2927.12, 2856.43, 1752.57, 1708.84, 1618.62, 1526.48, 1451.97, 1273.72, 1087.35cm-1. ESIMS, m/z: 263 (MH+). Anal. Calcd for C14H18N2OS: C, 64.09; H, 6.91; N, 10.68. Found: C, 64.08; H, 6.95; N, 10.58.
3-Butyl-5-isobutyl-2-thioxoimidazolidin-4-one (4i). 1H NMR (CDCl3): δ = 4.12 (t, 2H, J = 7 Hz), 3.73 (m, 1H), 2.02 (m, 2H), 1.62 (m, 1H), 1.43 (m, 2H), 1.33 (m, 2H), 1.25 (m, 3H), 0.97 (d, 6H, J = 7 Hz). IR (neat): 3448.12, 2959.02, 2861.73, 1684.66, 1459.49, 1399.47, 1201.82, 1138.24, 837.82, 754.35cm-1. ESIMS, m/z: 229 (MH+). Anal. Calcd for C11H20N2OS: C, 57.86; H, 8.83; N, 12.27. Found: C, 57.93; H, 8.91; N, 12.17.
3-Phenyl-2-thioxoimidazolidin-4-one (4j). 1H NMR (CDCl3): δ = 7.38 (m, 5H), 7.01 (m, 1H), 3.79 (s, 2H). IR (neat): 3032.50, 2972.59, 2927.55, 1715.14, 1526.43, 1404.32, 1319.61, 1256.09, 1133.83cm-1. ESIMS, m/z: 193 (MH+). Anal. Calcd for C9H8N2OS: C, 56.23; H, 4.19; N, 14.57. Found: C, 56.13; H, 4.21; N, 14.47.
2-Thioxo-3-m-(tolyl)imidazolidin-4-one (4k). 1H NMR (CDCl3): δ = 7.39 (m, 1H), 7.26 (m, 2H), 7.12 (m, 2H), 3.77 (s, 2H), 2.40 (s, 3H). IR (neat): 3374.31, 2960.61, 1746.93, 1605.41, 1492.70, 1392.90, 1355.74, 1268.56, 1235.06 cm-1. ESIMS, m/z: 207 (MH+). Anal. Calcd for C10H10N2OS: C, 58.23; H, 4.89; N, 13.58. Found: C, 58.33; H, 4.89; N, 13.49.

ACKNOWLEDGEMENTS
This work was supported by the Natural Science Foundation of China (grant No. 20862004), by the Key Project of Science and Technology of Guizhou Province (grant No. 2007-2022), and by the Special Scientific Research Foundation of Guizhou Province (grant No. TZJF-2006.25).

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